Acromegaly, a disorder of chronic, excessive growth hormone section, is associated with significant morbidity and mortality. Prevention of the long-term complications of this disease depends on both accurate biochemical assessment of disease status and effective treatment. This proposal will examine new approaches to the evaluation and treatment of acromegaly utilizing a cohort of 135 patients previously treated surgically. My preliminary biochemical assessment in 60 of these patients has raised important new questions about the reliability of previously accepted guidelines for cure and has identified the need for new therapy for this disease. Specific aim 1 focuses on a careful biochemical assessment of this cohort with new, sensitive techniques in order to re-assess the criteria for cure. A second aim is to evaluate treatment with a promising new dopamine agonist, cabergoline, in patients with clearly active disease. A third aim is to analyze stored tumor specimens from this large cohort for the presence of activating mutations in the alpha subunit of Gs to determine if mutations define a clinical phenotype and/or biochemical response to cabergoline. The essence of this project, namely evaluation of criteria to define cure with modern assays and evaluation of new therapeutic options in association with molecular analysis of tumors has not previously been conducted. We expect these studies to yield important new information about the definition of cure, optimal therapeutic endpoints and treatment options for acromegaly. I plan an investigative career in academic medicine focusing on neuroendocrinology and pituitary disease. My goal is to become an independent investigator. This award will enable me to obtain new research skills in two areas, clinical research method and molecular analysis, and will set the groundwork for future studies which are essential for me to reach this goal. My current environment is ideally suited for achieving this goal. Through Dr. Kalmon Post, I have access to a large cohort of patients who have had pituitary surgery. I also have access to a large number of carefully stored tumor specimens with which I can learn the molecular techniques and study the issues raised in this project. I will receive instruction in the techniques necessary for the molecular analysis from Drs. Sharon Wardlaw and Streamson Chua. Our Endocrinology Division, with a distinguished tradition in the neuroendocrine research, is an excellent environment in which to engage in clinical research. My sponsor, Dr. Wardlaw, is highly qualified and committed to providing me with the support I need to pursue my research plans and to facilitate my transition to independent investigator.